The Dynamics of Human Atrial Fibrillation Project Summary Atrial fibrillation (AF) is the most common heart rhythm disorder, affecting over 5 million Americans in whom it may cause skipped heart beats, dizziness, stroke and even death. Unfortunately, therapy for AF is limited. One of the major drawbacks in developing better therapy for AF is that our understanding of what causes AF (its 'mechanisms') is not clear. This project tests the novel hypothesis that human AF is not a random or chaotic rhythm disorder, but instead is caused by a small number of 'sources', in the form of 'rotors' (akin to electrical spinning tops) or focal beats, that are stable in the heart over time. Sources may lie in regions o the heart (the 'atria', or top chambers) that vary between patients, often away from where physicians currently target treatment such as ablation (cautery). This project is a renewal of the applicant's prior project that tested the conditions that may enable stable sources to form in patients with atrial fibrillation. In this project, we will 1) test in patients undergoing clinicaly prescribed ablation, if ablation stops (terminates) AF when sources are ablated (cauterized), or whether AF stops because 'chaotic' mechanisms are organized by ablation; 2) determine how ablation is actually able to abolish rotors or focal sources, or organize 'chaotic' wavelets; 3) tet in a clinical trial if ablation that adds ablation of sources to conventional ablation improves the successful elimination of AF on careful follow-up. We will pursue these aims by obtaining high-quality electrophysiologic and anatomic data in patients with AF and control subjects with other rhythm disturbances, performing numerical analyses and developing computer models. The patient-specific digital computer models that we will create in this project will be among the most detailed and clinically-relevant in the field, and can be used by others to understand the disease and help design better therapy. This project is significant because it will establish a new mechanism for human atrial fibrillation and test whether elimination of this mechanism can eliminate the clinical disorder. Understanding AF at this level may also allow a more rational approach to drug development and gene therapy. This project will be performed in patients during electrophysiologic study, so that its results can be translated directly to practice.